It is estimated that a third of the world's population is infected with Mycobacteria tuberculosis, the causative agent of tuberculosis (TB), and between 5-10% of those infected individuals will develop the active disease over their lifetime. As a result, TB is the second leading cause of death from an infectious disease and the leading cause of death from a bacterial infection worldwide. In addition to the global burden, the increasing rates of multi-drug resistant strains (MDR) that require extensive treatment regimens with second line drugs impacts disease management. Therefore, there is a need to develop new therapeutics with unique modes of action that can be used to treat TB or that can be co-administered with existing antitubercular drugs.
Cell division is an attractive target for the development of new chemotherapeutics against pathogenic bacteria, which are often medically important, difficult to treat, and drug resistant. One example is Mycobacteria tuberculosis. Of all the components involved in bacterial cell division two proteins, FtsZ and FtsI, are the best characterized and are therefore receiving the most attention with regards to drug discovery. Although, FtsZ and tubulin share structural and functional homology, specificity for the mycobacterial FtsZ can be obtained through medicinal chemistry efforts (Huang et al., J. Med. Chem. 2006; 49:463-466; Kumar et al., J. Med. Chem. 2011; 54:374-381). This specificity affords the opportunity to use known pharmacophores such as pyridopyrazine, pteridine and benzimidazole as starting points for SAR optimization. Certain 2,5,6- and 2,5,7-trisubstituted benzimidazoles developed through rational drug design have demonstrated potency with low or negligible cytotoxicity. However, the determination of their in vivo efficacy cannot be determined by analysis of their minimal inhibitory concentrations (MIC) alone, and adequate in vitro methods for determining in vivo efficacy are urgently needed.